DESCRIPTION (provided by applicatnt): Bullous pemphigoid (BP) are life-threatening blistering diseases that are characterized by the presence of sub-epidermal vesicles and complement-activating autoantibodies directed against the hemidesmosomal proteins, BP180 and BP230. BP autoantibodies are predominant IgG and IgE. Human BP and BP animal model studies have suggested that the key pathogenic elements of these diseases include autoantibody reactivity to BP180, complement, mast cells, and neutrophils/eosinophils. Neutrophil elastase, MMP-9, and plasmin/plasminogen system are directly involved in tissue injury at the basement membrane, resulting in dermal-epidermal junction separation. The long-term goal of this project is to increase our understanding of the pathophysiology and autoimmunity of BP and how it relates to the functions of autoantibodies and proteinases in inflammation and autoimmunity. The objective of this application is to study role of proteolytic enzymes, isotype and subclass of pathogenic BP autoantibodies using the rabbit anti-mBP180 IgG passive transfer model and our newly developed humanized BP180NC16A mouse model. Aim 1 is to study the role of mast cell proteinases using rabbit anti-mBP180 IgG passive transfer model. Pathogenic rabbit anti-mBP180 IgG antibodies will be injected into mice deficient in different mast cell proteinases. Degradation of BP180 and other key extracellular matrix components by these proteolytic enzymes will be determined. Aim 2 is to directly test the pathogenic activity of autoantibodies from BP patients'sera in humanized BP180NC16A mice, in which mBP180NC14A is replaced with hBP180NC16A. Pathogenic epitopes and IgG subclasses of human BP autoantibodies will also be identified by using the humanized mice. Aim 3 is to test whether anti-BP180 IgE autoantibodies and eosinophils play a part in the disease process. Aim 4 is to test pathogenicity of anti-BP180 autoantibodies from patients with herpes gestationis. Findings from these proposed studies will significantly increase our understanding of the disease mechanisms and help develop more specific and effective and less side-effect therapies for BP patients. Bullous pemphigoid (BP) is the most common and potentially fatal autoimmune blistering disease. Better understanding of the disease process will lead to more effective therapies.